This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Structure-based drug design of potent botulinum neurotoxin inhibitors. The neurotoxin produced by the soil-dwelling bacterium Clostridium botulinum is among the most potent toxins known. The toxin is a zinc-dependent endoprotease that disrupts vesicle trafficking at the neuromuscular synapses, effectively blocking neurotransmitter release and leading to the characteristic flaccid paralysis of botulism. In collaboration with groups at Tufts University School of Veterinary Medicine, Absolute Science (Lexington, MA), the Laboratory for Drug Discovery in Neurodegeneration at Harvard University, and the Scripps Research Institute, lead compounds with significant inhibitory activity against the neurotoxin have been identified by library screening. The X-ray crystal structures of the C. botulinum neurotoxin (BoNT) serotype A protease in complex with a number of lead compounds have been determined and led to the development of a potent BoNT/A inhibitor.